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G2019S LRRK2 mutation facilitates α-synuclein neuropathology in aged mice

Novello, Salvatore and Arcuri, Ludovico and Dovero, Sandra and Dutheil, Nathalie and Shimshek, Derya and Bezard, Erwan and Morari, Michele (2018) G2019S LRRK2 mutation facilitates α-synuclein neuropathology in aged mice. Neurobiology of disease, 120. pp. 21-33. ISSN 09699961

Abstract

Fibrillization of α-synuclein is instrumental for the development of Parkinson's disease (PD), thus modulating this process can have profound impact on disease initiation/progression. Here, the impact of the p.G2019S mutation of leucine-rich repeat kinase 2 (LRRK2), which is most frequently associated with familial and sporadic PD, on α-synuclein pathology was investigated. G2019S knock-in mice and wild-type controls were injected with a recombinant adeno-associated viral vector serotype 2/9 (AAV2/9) overexpressing human mutant p.A53T α-synuclein (AAV2/9-hα-syn). Control animals were injected with AAV2/9 carrying green fluorescent protein. Motor behavior, transgene expression, α-syn and pSer129 α-syn load, number of nigral dopamine neurons and density of striatal dopaminergic terminals were evaluated. To investigate the effect of aging, experiments were performed in 3- and 12-month-old mice, evaluated 20 and 12 weeks after virus injection, respectively. hα-syn overexpression induced progressive motor deficits, loss of nigral dopaminergic neurons and striatal terminals, and appearance of proteinase K-resistant aggregates of pSer129 α-syn in both young and old mice. Although no genotype difference was observed in 3-month-old mice, degeneration of nigral dopaminergic neurons was higher in 12-month-old G2019S knock-in mice compared with age-matched wild-type controls (−55% vs −39%, respectively). Consistently, a two-fold higher load of pSer129 α-syn aggregates was found in 12-month-old G2019S knock-in mice. We conclude that G2019S LRRK2 facilitates α-synucleinopathy and degeneration of nigral dopaminergic neurons, and that aging is a major determinant of this effect.

Item Type: Article
Keywords: G2019S knock-in mice iba-1 LRRK2 Microglia Parkinson's disease α-synuclein
Date Deposited: 12 Feb 2019 00:45
Last Modified: 12 Feb 2019 00:45
URI: https://oak.novartis.com/id/eprint/36861

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